1. Field of the Invention
The present disclosure relates to a composition comprising Trigoneoside Ib and Vicenin-1 and the method of obtaining the said composition. The present disclosure further relates to the application of the composition for treatment and management of autoimmune disorders such as Goodpasture's disease, Glomerulonephritis, Rheumatoid Arthritis, Systemic Lupus Erythematosus and Idiopathic Thrombocytopenia Purpura.
2. Description of the Related Art
Autoimmune disorders such as Goodpasture's disease, Glomerulonephritis, Rheumatoid Arthritis, Systemic Lupus Erythematosus and Idiopathic Thrombocytopenia Purpura demonstrate excessive production of auto-antibodies that cause severe damage to cells, tissues, organs etc. These diseases are characterized by loss of body's tolerance towards self-antigens and subsequent activation of immune responses leading to damage. Hereditary predispositions and environmental factors are predominant causes of these diseases.
Goodpasture's disease and glomerulonephritis are characterized by deposition of antibodies along the glomerular basement membrane (GBM) in the kidneys resulting in extracapillary glomerulonephritis. These diseases are commonly termed as anti-glomerular basement membrane (anti-GBM) diseases. Patients suffering from anti-GBM diseases have only 10% chance of renal survival. Goodpasture's disease is a rare disease occurring in one in million people. Auto-antibodies mediated kidney damage is the primary concern in Goodpasture's disease. Some patients also develop pulmonary hemorrhage however the damage caused to lungs by anti-GBM antibodies is not permanent and rarely fatal when compared to damage to the kidneys.
Existing treatment for Goodpasture's disease or glomerulonephritis includes plasmapheresis or plasma exchange procedure which eliminates circulating anti-GBM antibodies from the blood. Risk of exposure to blood products, hematoma, transfusion reaction, and transfusion transmitted diseases are major complications which are associated with plasmapheresis. Other treatment options include administration of immunosuppressive agents like corticosteroids and cyclophosphamide which are prescribed to manage progressive kidney failure and bleeding in the lungs. These drugs suppress immune response in a non-specific way and increase the chances of patients getting opportunistic infections. Current line of treatment for anti-GBM diseases does not completely control the disease. Progression of the disease to end stage organ failure increases the risk of mortality.
Rheumatoid Arthritis (RA) is a chronic, progressive disease affecting about 1% of the world's population which is mediated through auto antibodies. Similar to Goodpasture's disease, RA is characterized by loss of body's tolerance towards self-antigens and subsequent activation of immune responses leading to tissue damage. Production of auto-antibodies targeting the synovial membrane, cartilage, and underlying bone joint defines pathogenesis of RA. Deformation of the joints results in severe disability and reduced quality of living. Common symptoms include joint pain, stiffness and swelling of joints, movement disability, muscle weakness, fever and general feeling of being unwell. Increased levels of C-reactive protein and rheumatoid factor in the blood are diagnostic indicators of RA. Existing treatment for RA include disease modifying anti-rheumatic drugs (DMARDs) like hydroxychloroquine, immunosuppressants like azathiprine, corticosteroids, selective COX-2 inhibitors, NSAIDs, and analgesics for symptomatic relief Chronic use of analgesics, NSAIDs cause ulcers and have low tolerance with most patients and selective COX-2 inhibitors are associated with cardiac toxicity.
Immunosuppressants are the major line of treatment for RA. As discussed earlier, these drugs suppress immune response in a non-specific way and give raise to life threatening complications. Biological drugs like TNF inhibitors namely adalimumab, etanercept, infliximab etc., IL-1 receptor antagonists namely Anakinra and IL-6 receptor antagonists namely tocilizumab are widely used in treating RA. These drugs are designed to affect the biochemical pathways that cause inflammation of joint and joint damage by acting as antagonists of the cytokine receptors. One major disadvantage of biologicals is that on chronic usage patients become refractive to these drugs and the efficacy of treatment declines. Due to the toxicity profile, many of these drugs are recommended only for patients who do not respond to other RA treatments.
Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disorder which is clinically diagnosed on the basis of features like joint pain, fever, fatigue, skin lesions, photosensitivity, chest pain, hair loss, mouth sores etc., supported by findings of auto-antibodies in the blood and excessive serum protein in the urine. Kidney failure is one of the major complications of SLE. More than 50% of SLE patients develop kidney failure due to deposition of antibodies in the glomeruli and require kidney dialysis or transplantation. Other complications mediated by auto-antibodies include damage to the lungs, heart, hemolytic anemia, thrombocytopenia, cerebral dysfunction etc. Existing treatment options for SLE includes NSAIDs, antimalarial agents, corticosteroids and methotrexate for alleviating musculo-skeletal and cutaneous manifestations. According to the USFDA, current line of treatment for SLE have issues like incompletely controlled disease, progression to end-stage organ failure and debilitating side effects (Guidance for Industry: Systemic Lupus Erythematosus—Developing Medical Products for Treatment, June 2010).
Idiopathic thrombocytopenia purpura (ITP) is a bleeding disorder caused by drastic reduction in platelets. ITP can be triggered by infections, immune disorders like SLE, certain drugs, pregnancy etc. Although the exact mechanism of ITP pathogenesis is still not clear, ITP is largely attributed to destruction of platelets by anti-platelet antibodies since more than 50% of ITP patients test positive for platelet associated antibodies (Gernsheimer, 2009). Existing treatment options for ITP include (i) drugs like corticosteroids and intravenous immunoglobulin which interfere with clearance of antibody-coated platelets; (ii) nonspecific T-cell immunosuppression by drugs like azathioprine, cyclophosphamide, cyclosporine; (iii) mycophenolate mofetil and biologicals like rituximab which interfere with antibody synthesis; (iv) spleenectomy and plasmapheresis procedures which clear circulating anti-platelet antibodies; (v) increasing platelet count by platelet transfusion and bone marrow transplantation etc. All the above treatment options have potential side effects such as suppression of immunity, exposure to blood products with risk of transfusion reactions and/or transfusion transmitted diseases and hematoma.
With the short-comings of existing treatment options for autoimmune disorders such as Goodpasture's disease, Glomerulonephritis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Idiopathic Thrombocytopenia Purpura etc., it is essential for drug companies to research and develop more effective treatment with lower side effects for resolution of these chronic, life-threatening diseases.
U.S. Pat. No. 6,080,401 by Malireddy S. Reddy et al., describes use of a composition consisting mixtures of several herbs one of which being Trigonella foenum-graecum, along with mixtures of several probiotic preparations for treatment of wide variety of diseases namely anemia, arthritis, constipation, depression, diabetes, dyspepsia, hemorrhoids, hepatitis, hypertension, impotency, overweight, periodontal disease and combinations thereof.
U.S. Pat. No. 5,707,631 by Chaim Lieberman discloses formulation of herbal composition consisting of Trigonella foenum-graecum, Syzygium aromatium fruit, Allium sativum bulb, Cinnamon zeylanicum bark, Saussurea costus root and Euphorbia lathyrus bud for use in lowering cholesterol, treating arthritis, blood pressure and alzheimer's disease. However, this patent document does not disclose any evidence which can be understood and practiced by anyone skilled in the art regarding any action of this composition in arthritis in this patent.
Chopra et al. (2010) has recently published a poly-herbal composition comprising extract of Trigonella foenum-graecum (Fenugreek) along with extracts of Boswellia serrata (Salai Guggul), Linum usitatissimum (Flaxseed), Camellia sinensis (Green tea), Curcuma longa (Turmeric), Tribulus terrestris (Gokshur) and Piper nigrum (Black pepper) used for treatment of RA.
Khan et al. (2011) clinically evaluated a herbal composition comprising Nigella sativa, Withania somnifera, Smilax china, Apium graveolens, Trigonella foenum graecum, Zingiber officinale and Colchicum autumnale for treatment of Rheumatoid Arthritis.
All the above discussed prior art discloses composition consisting of several herbs and it is difficult to establish that the Trigonella foenum-graecum is contributing to the beneficial effects claimed.
Trigonella foenum-graecum or fenugreek is most commonly used in traditional medicine. Extracts of fenugreek seeds are investigated for treatment of various diseases like diabetes, gout, stomach ulcers, diarrhea, constipation etc. Ahmadiani et al. (2001) studied the anti-inflammatory and anti-pyretic activity of fenugreek. Vyas et al. (2008) showed that extract of fenugreek seeds have analgesic and anti-inflammatory activities. These studies do not illustrate or teach specific components or chemical composition in fenugreek seeds which contribute to the claimed activities.
Fenugreek seeds are composed of many chemical substances namely Alkaloids like Trigonelline, Gentianine, Carpaine, Choline; Amino acids like 4-Hydroxyisoleucine, Histidine, Lysine, Arginine; Flavonoids—Luteolin, Quercetin, Vitexin, Isovitexin, Orientin, Isoorientin, Vicenin-1, Vicenin-2; Furostanol Saponins—Triogenelloside C, Trigofoenosides, Trigoneosides, Fenugrin B; Spirostanol Saponins-Graecunins, Fenugreekine; Sapinogens—Diosgenin, Yamogenin, Yuccagenin, Lilagenin, Tigogenin, Neotigogenin, Gitogenin, Neogitogenin, Sarsasapogenin, Smilagenin; Anthocyanins; Fiber—Gum; Other phenolic components—Trigocoumarin, Scopoletin, Chlorogenic, Caffeic and p-Coumaric acids; Lipids; Vitamins and traces of inorganic elements.
The main embodiment of the present disclosure is a composition comprising Trigoneoside Ib and Vicenin-1 for treatment of autoimmune disorders such as Goodpasture's diseases, Glomerulonephritis and Rheumatoid Arthritis. The novelty and inventiveness of this disclosure resides in the unique composition of Trigoneoside Ib and Vicenin-1. Trigoneoside Ib has been reported as one of the many furostanol saponins present in fenugreek seeds. Structure of Trigonesoide Ib is shown in FIG. 1. Yoshikawa et al. (1997) and Murakami et al. (2000) have characterized all the Trigoneosides present in fenugreek and reported 13C NMR, 1H NMR and [α]D data for these molecules. Trigoneoside Ia, Ib and XIb are structural isomers with molecular weight of 906 with comparable NMR data and different [α]D data. Identification of specific isomer can be carried out using acid hydrolysis in which Trigoneoside Ia gives a neogitogenin, Trigoneoside Ib gives a gitogenin and Trigonesoside XIb gives an L-rhamnose.
Many flavonoid glycosides are present in fenugreek seed namely vitexin, isovitexin, orientin, isoorentin, vicenin etc. These flavonoids have been investigated for various physiological activities like anti-oxidative, anti-thyroid, anti-apoptic, anti-inflammatory, anti-nociceptive, anxiolytic etc. The present disclosure is related to one of the flavonoid glycoside Vicenin-1. Presence of Vicenin-1 in fenugreek is reported by Wagner et al. (1973). Structure of Vicenin-1 is shown in FIG. 2. Other plant species containing Vicenin-1 are Linum usitatissimum, Tragopogon porrifolius and Triticum aestivum. Sato et al. (2010) has disclosed a method of synthesis of Vicenin-1 and provided comparative data of 13C NMR for synthetic and naturally obtained Vicenin-1.